This application is a 371 of PCT/JP00/00675 filed Feb. 8, 2000.
The present invention relates to a cell death inhibitor capable of inhibiting cell death induced by various substances in living body or foreign stimulants, or stimuli such as temperature, radiation and so on; its use as drugs for treating neurodegenerative diseases, diseases of circulatory organs, hepatitis, renal diseases, inflammatory skin disorders, radiation disorders, viral diseases, prion diseases, functional deficiency of transplanted organs, or the like, or preventing progress of the symptoms of the diseases; use as preservatives for organs, tissues and cells isolated from a living body.
Recent progress of the study as to cell death have revealed that cell death of cells essential for living body, particularly apoptosis is involved in progress and exacerbation of a variety of diseases (Science, Vol. 267, p. 1456, 1995). Apoptosis is a type of cell death in which cells commit a death using their own molecular machinery, characterized generally by (1) chromatin aggregation, (2) cell shrinkage, (3) blebbing of plasma membrane (formation of processes), (4) nuclear fragmentation, (5) formation of apoptotic bodies, (6) DNA fragmentation, and (7) phagocytosis (scavenging cell debris) by neighboring cells and macrophages. In contrast, there is another type of cell death, called necrosis, characterized by cell swelling and lysis, which occurs without executing the apoptotic processes when cells are exposed to excessive radiation, heat, noxious stimulants or the like. However, the cell death caused by the own molecular machinery does not always show a full set of the apoptosis characteristics described above, depending on species of cells, environments under which cells are present, and species and strength of cell death stimulants. Likewise, necrosis in view of pathology sometimes contains a cell death which some own molecular machinery is responsible for. In the invention, such cell death is also included in apoptosis.
Examples of the diseases whose progress and exacerbation are caused by apoptotic cell death are as follows: neurodegenerative diseases such as Alzheimer""s disease [Bio Science terminology library: apoptosis/separate volume of xe2x80x9cJikken Igaku (Experimental Medicine)xe2x80x9d, p. 168, 1996], spinal muscular atrophy (SMA) [Bio Science terminology library: apoptosis/separate volume of xe2x80x9cJikken Igaku (Experimental Medicine)xe2x80x9d, p. 173, 1996], amyotrophic lateral screrosis (ALS) [Bio Science terminology library: apoptosis/separate volume of xe2x80x9cJikken Igaku (Experimental Medicine)xe2x80x9d, p. 176, 1996], Parkinson""s disease (J. Neurochem., Vol. 69, p. 1612, 1997), Huntington""s disease (J. Neurosci., Vol. 15, p. 3775, 1995), pigmentary degeneration of the retina and glaucoma [Bio Science terminology library: apoptosis/separate volume of xe2x80x9cJikken Igaku (Experimental Medicine)xe2x80x9d, p. 196, 1996], cerebellar degeneration and neonatal jaundice (Progress in Drug Research, Vol. 48, p. 55, 1997); myasthenia gravis (J. Clinical Investigation, Vol. 99, p. 2745, 1997); brain ischemia from apoplexy and the like, and successive delayed neuronal death (DND) [Bio Science terminology library: apoptosis/separate volume of xe2x80x9cJikken Igaku (Experimental Medicine)xe2x80x9d, p. 180, p. 182, 1996], ischemic heart disease due to myocardial infarction (myocardial ischemia and disorder after reperfusion), viral myocarditis, autoimmune myocarditis (congestive cardiomyopathy and chronic myocarditis), myocardial disorders or death due to hypertrophic heart and heart failure, arrythmogenic right ventricular cardiomyopathy [Bio Science terminology library: apoptosis/separate volume of xe2x80x9cJikken Igaku (Experimental Medicine)xe2x80x9d, p. 198, 1996; xe2x80x9cKekkan to Naihi (Blood Vessel and Endothelium), Vol. 7, p. 357, p. 364, p. 370, 1997]; alcoholic hepatitis, viral hepatitis [Bio Science terminology library: apoptosis/separate volume of xe2x80x9cJikken Igaku (Experimental Medicine)xe2x80x9d, p. 190, 1996], renal diseases such as glomerulonephritis, hemolytic uremic syndrome and the like [Bio Science terminology library: apoptosis/separate volume of xe2x80x9cJikken Igaku (Experimental Medicine)xe2x80x9d, p. 192, 1996], acquired immunodeficiency syndrome (AIDS) [Bio Science terminology library: apoptosis/separate volume of xe2x80x9cJikken Igaku (Experimental Medicine)xe2x80x9d, p. 156, 1996; xe2x80x9cKetsueki, Meneki, Shuyou (Blood, Immunity, Cancer)xe2x80x9d, Vol.2, p. 432, 1997], inflammatory skin disorders such as toxic epidermal necrolysis (TEN) and multiform exudative erythema, alopecia, graft versus host disease (GVH) [Bio Science terminology library: apoptosis/separate volume of xe2x80x9cJikken Igaku (Experimental Medicine)xe2x80x9d, p. 194, 1996], radiation disorders [Bio Science terminology library: apoptosis/separate volume of xe2x80x9cJikken Igaku (Experimental Medicine)xe2x80x9d, p. 160, 1996], side effects due to anti-cancer drugs, anti-viral drugs and the like, disorders due to toxic agents such as sodium azide, potassium cyanide and the like [Bio Science terminology library: apoptosis/separate volume of xe2x80x9cJikken Igaku (Experimental Medicine)xe2x80x9d, p. 162, 1996], sepsis (Critical Care Medicine, Vol. 25, p. 1298, 1997), osteomyelo-dysplasia such as aplastic anemia and the like (Leukemia, Vol. 7, p. 144, 1993), insulin dependent diabetes (Diabetes, Vol. 44, p. 733, 1995), prion diseases such as Creutzfeldt-Jakob""s disease (J. Neural Transmission, Supplementum, Vol. 50, p. 191, 1997), and so on. In organ transplantation, it has been suggested that apoptosis due to reactive oxygen species and various chemical mediators generated after reperfusion of anoxic organs by isolation or cardiac arrest of a donor is responsible for functional deficiency of transplanted organs (for example, xe2x80x9cIshoku (Transplantation)xe2x80x9d, Vol. 27, p. 15, 1992). Probably, rejection reaction after transplantation of an organ, tissues, or cells may be a result of apoptosis of the transplanted cells, which occurs when they are attacked by recipient immune cells. It is thus reasonably concluded that chemical compounds capable of inhibiting cell death can be a promising drug that heals these diseases effectively, or inhibits or stops progress and exacerbation of the symptoms of these diseases.
In the transplantation of organs or tissues, graft survival rate after transplantation depends on the preserving conditions of the organs or tissues isolated from a donor. Accordingly, it is expected to improve organ and tissue preservation by adding chemical compounds inhibiting cell death into preservation liquids for the organs and tissues. Unlike immortalized cells or cancer cells, primary cultured cells isolated from a living body are usually difficult to culture in vitro. For long time cultivation, appropriate concentration of additives including various growth factors are required in the culture medium depending on species of the cells, and apoptosis easily occurs in case that the culture conditions are improper. When cells are cultured for research or medical purposes, it is expected that addition of a chemical compound inhibiting cell death would lead successful cell cultivation.
Apoptosis is known to be triggered by a wide variety of physiological substances such as cytokines including interleukins, hormones including glucocorticoids, excitotoxic amino acids including glutamic acid and NMDA, and membrane proteins represented by Fas ligand, depending on cell types. It is also triggered by deprivation of a specific growth factor or the like in some cell types. There are common apoptosis triggers irrespective of cell type, such as reactive oxygen species generators including hydrogen peroxide and the like, NO generators including SNP and the like, heat, and radiation. A number of chemical compounds are also reported to be able to induce apoptosis. Recent studies have shown that apoptotic signal transduction systems where a variety of signal transduction systems participate at the upstream, appear to converge on caspase activating mechanisms at the downstream, the caspases being a series of cysteine protease (Cell, Vol. 91, p. 443, 1997), though their precise molecular mechanisms should be investigated in future.
Substances heretofore known as apoptosis inhibitors are, depending on species of the cells, a variety of growth factors and nutrient factors, physiological inhibitors such as hormones and the like, antioxidants such as N-acetyl-cysteine and the like, and modified peptide-type caspase inhibitors. Among them, some of peptide-type growth factors and neurotropic factors have been clinically used for the recovery of hematopoietic cells depleted after chemotherapy and for preventing cell death of neurons from neuro-degenerative diseases and trauma (Proc. Natl. Acad. Sci. U.S.A., Vol. 90, p. 7951, 1993; Nature, Vol. 367, p. 368, 1994; Proc. Natl. Acad. Sci. U.S.A., Vol. 89, p. 11249, 1992). The antioxidants and caspase inhibitors are only used in experiments of the cell level. Thus, it has been desired to develop an apoptosis inhibitor which is more stable in vivo, orally active, and a non-peptide type as well as low in molecular weight. Furthermore, since it is rare case that all apoptosis-triggering physiological factors and its inhibiting factors of the individual cells have been successfully identified in actual diseases, there is a demand for an entirely new type of cell death inhibitor which is also expected to be beneficial for the diseases where the factors are unidentified.
At present, Euro-Collins""solution and University of Wisconsin solution are generally used as organ preservation solutions for transplantation (xe2x80x9cIShoku (Transplantation)xe2x80x9d, Vol. 27, p. 172, 1992). Supplementation of antioxidants and radical scavengers to such preservation solutions in order to ameliorate damages of reactive oxygen has been reported to have beneficial effects on organ preservation (for example, xe2x80x9cIShoku (Transplantation)xe2x80x9d, Vol. 27, p. 15, 1992; Vol. 26, p. 62, 1991; Vol. 25, p. 596, 1990; Trans Proc., Vol. 17, p. 1454, 1985). However, the organ preservation is not fully sufficient, and higher graft survival rate is still desired.
The invention aims to provide a compound useful for inhibiting death of cells, the drug being expected as a preventive or a remedy for the progress of various diseases wherein cell death participates in progress and exacerbation thereof.
As a result of the extensive studies for achieving the above, the present inventors have found that the below-mentioned bisindolylpyrrole derivatives exhibit a cell death inhibiting action and have accomplished the invention.
Namely, the invention provides a bisindolylpyrrole derivative represented by the following formula [I] 
wherein, R1 and R2 each independently represents hydrogen atom, an alkyl group which may possess substituent(s), an alkenyl group which may possess substituent(s), an alkynyl group which may possess substituent(s), an aryl group which may possess substituent(s), an acyl group which may possess substituent(s), an acyloxy group which may possess substituent(s), an alkoxy- or aryloxycarbonyl group which may possess substituent(s), an alkyl- or arylthiocarbonyl group which may possess substituent(s), an aminocarbonyl group which may possess substituent(s), an aminocarbonyloxy group which may possess substituent(s), an alkyl- or arylsulfonyl group which may possess substituent(s), an alkoxyl group which may possess substituent(s), an aryloxy group which may possess substituent(s), or hydroxyl group; R3 and R4 each represents substituent(s) on an indole ring, and represents, number and position (2-, 4-, 5-, 6-, or 7-position as position number of the indole ring) of the substituent(s) and kinds of the substituent(s) may be the same or different, hydrogen atom, an alkyl group which may possess substituent(s), an alkenyl group which may possess substituent(s), an alkynyl group which may possess substituent(s), an aryl group which may possess substituent(s), an acyl group which may possess substituent(s), an acyloxy group which may possess substituent(s), an alkoxy- or aryloxycarbonyl group which may possess substituent(s), an alkoxy- or aryloxycarbonyloxy group which may possess substituent(s), an alkyl- or arylthiocarbonyl group which may possess substituent(s), an aminocarbonyl group which may possess substituent(s), an aminocarbonyloxy group which may possess substituent(s), an alkyl- or arylsulfonyl group which may possess substituent(s), an alkyl- or arylsulfinyl group which may possess substituent(s), an alkoxyl group which may possess substituent(s), an aryloxy group which may possess substituent(s), an alkyl- or arylthio group which may possess substituent(s), hydroxyl group, carboxyl group, oxysulfonyl group, cyano group, nitro group, an amino group which may possess substituent(s), or a halogen atom; R1 and R2, R1 and R3, R2 and R4, R3 and R6, R4 and R6, R5 and R6, two R3, or two R4 may be combined to form a hydrocarbon chain or a hydrocarbon chain containing heteroatom(s) which may possess substituent(s); R5 represents hydrogen atom, an alkyl group which may possess substituent(s), an alkenyl group which may possess substituent(s), an alkynyl group which may possess substituent(s), an aryl group which may possess substituent(s), hydroxyl group, an alkoxyl group which may possess substituent(s), an aryloxy group which may possess substituent(s), an amino group which may possess substituent(s), an acyl group which may possess substituent(s), an acyloxy group which may possess substituent(s), an alkoxy- or aryloxycarbonyl group which may possess substituent(s), an alkyl- or arylthio group which may possess substituent(s), an aminocarbonyl group which may possess substituent(s), an alkyl- or arylsulfonyl group which may possess substituent(s); R6 represents substituent(s) on a pyrrole ring (at 2-, 5-, or both position(s) as position numbering of pyrrole ring, in the last case substituents may be the same or different), hydrogen atom, an alkyl group which may possess substituent(s), an alkenyl group which may possess substituent(s), an alkynyl group which may possess substituent(s), an aryl group which may possess substituent(s), an acyl group which may possess substituent(s), an acyloxy group which may possess substituent(s), an aryloxycarbonyl group which may possess substituent(s), an aryloxycarbonyloxy group which may possess substituent(s), an alkyl- or arylthiocarbonyl group which may possess substituent(s), an aminocarbonyl group which may possess substituent(s), an aminocarbonyloxy group which may possess substituent(s), an alkyl- or arylsulfonyl group, an alkyl- or arylsulfinyl group which may possess substituent(s), an alkoxyl group which may possess substituent(s), an aryloxy group which may possess substituent(s), an alkyl- or arylthio group which may possess substituent(s), hydroxyl group, carboxyl group, oxysulfonyl group, cyano group, nitro group, an amino group which may possess substituent(s), or a halogen atom.
The invention also provides a cell death inhibitor comprising, as an active ingredient, a bisindolylpyrrole derivative represented by the following formula [II] or a pharmaceutically acceptable salt thereof 
wherein, R1 and R2 each independently represents hydrogen atom, an alkyl group which may possess substituent(s), an alkenyl group which may possess substituent(s), an alkynyl group, which may possess substituent(s), an aryl group which may possess substituent(s), an acyl group which may possess substituent(s), an acyloxy group which may possess substituent(s), an alkoxy- or aryloxycarbonyl group which may possess substituent(s), an alkyl- or arylthiocarbonyl group which may possess substituent(s), an aminocarbonyl group which may possess substituent(s), an aminocarbonyloxy group which may possess substituent(s), an alkyl- or arylsulfonyl group which may possess substituent(s), an alkoxyl group which may possess substituent(s), an aryloxy group which may possess substituent(s), or hydroxyl group; R3 and R4 each represents substituent(s) on an indole ring, and represents, number and position (2-, 4-, 5-, 6-, or 7-position as position number of the indole ring) of the substituent(s) and kinds of the substituent(s) may be the same or different, hydrogen atom, an alkyl group which may possess substituent(s), an alkenyl group which may possess substituent(s), an alkynyl group which may possess substituent(s), an aryl group which may possess substituent(s), an acyl group which may possess substituent(s), an acyloxy group which may possess substituent(s), an alkoxy- or aryloxycarbonyl group which may possess substituent(s), an alkoxy- or aryloxycarbonyloxy group which may possess substituent(s), an alkyl- or arylthiocarbonyl group which may possess substituent(s), an aminocarbonyl group which may possess substituent(s), an aminocarbonyloxy group which may possess substituent(s), an alkyl- or arylsulfonyl group which may possess substituent(s), an alkyl- or arylsulfinyl group which may possess substituent(s), an alkoxyl group which may possess substituent(s), an aryloxy group which may possess substituent(s), an alkyl- or arylthio group which may possess substituent(s), hydroxyl group, carboxyl group, oxysulfonyl group, cyano group, nitro group, an amino group which may possess substituent(s), or a halogen atom; R1 and R2, R1 and R3, R2 and R4, R3 and R7, R4 and R7, R5 and R7, two R3, or two R4 may be combined to form a hydrocarbon chain or a hydrocarbon chain containing heteroatom(s) which may possess substituent(s); R5 represents hydrogen atom, an alkyl group which may possess substituent(s), an alkenyl group which may possess substituent(s), an alkynyl group which may possess substituent(s), an aryl group which may possess substituent(s), hydroxyl group, an alkoxyl group which may possess substituent(s), an aryloxy group which may possess substituent(s), an amino group which may possess substituent(s), an acyl group which may possess substituent(s), an acyloxy group which may possess substituent(s), an alkoxy- or aryloxycarbonyl group which may possess substituent(s), an alkyl- or arylthiocarbonyl group which may possess substituent(s), an aminocarbonyl group which may possess substituent(s), an alkyl- or arylsulfonyl group which may possess substituent(s); R7 represents substituent(s) on a pyrrole ring (at 2-, 5-, or both position(s) as position nymbering of pyrrole ring, in the last case substituents may be the same or different), hydrogen atom, an alkyl group which may possess substituent(s), an alkenyl group which may possess substituent(s), an alkynyl group which may possess substituent(s), an aryl group which may possess substituent(s), an acyl group which may possess substituent(s), an acyloxy group which may possess substituent(s), an alkoxy- or an aryloxycarbonyl group which may possess substituent(s), an alkoxy- or an aryloxycarbonyloxy group which may possess substituent(s), an alkyl- or arylthiocarbonyl group which may possess substituent(s), an aminocarbonyl group which may possess substituent(s), an aminocarbonyloxy group which may possess substituent(s), an alkyl- or arylsulfonyl group, an alkyl- or arylsulfinyl group which may possess substituent(s), an alkoxyl group which may possess substituent(s), an aryloxy group which may possess substituent( s), an alkyl- or arylthio group which may possess substituent(s), hydroxyl group, carboxyl group, oxysulfonyl group, cyano group, nitro group, an amino group which may possess substituent(s), or a halogen atom; a drug for treating or preventing progress of symptoms, through inhibiting death of neurons, of neurodegenerative diseases such as Alzheimer""s disease, spinal muscular atrophy (SMA), amyotrophic lateral screrosis (ALS), Parkinson""s disease, Huntington""s disease, pigmentary degeneration of the retina, glaucoma, or cerebellar degeneration; a drug for treating or preventing progress of symptoms, through inhibiting death of neurons, of neonatal jaundice; a drug for treating or preventing progress of symptoms, through inhibiting death of cells, of myasthenia gravis; a drug for treating or preventing progress of symptoms, through inhibiting death of neurons, of brain ischemia from apoplexy and the like, and successive delayed neuronal death (DND); a drug for treating or preventing progress of symptoms, through inhibiting death of myocardial cells, of ischemic heart disease due to myocardial infarction, viral myocarditis, autoimmune myocarditis, myocardial disorders or death due to hypertrophic heart and heart failure, or arrythmogenic right ventricular cardiomyopathy; a drug for treating or preventing progress of symptoms, through inhibiting death of hepatic cells, of alcoholic hepatitis or viral hepatitis; a drug for treating or preventing progress of symptoms, through inhibiting death of renal cells, of renal diseases such as glomerulonephritis, hemolytic uremic syndrome and the like; a drug for treating or preventing progress of symptoms, through inhibiting excessive death of T-cells, of acquired immunodeficiency syndrome (AIDS); a drug for treating or preventing progress of symptoms, through inhibiting cell death, of inflammatory skin disorders such as toxic epidermal necrolysis (TEN), multiform exudative erythema and the like, alopecia, or graft versus host disease (GVH); a drug for treating or preventing disorders or side effects, through inhibiting cell death, of radiation disorders or disorders due to toxic agents including side effects due to drugs such as anti-cancer drugs, anti-viral drugs and the like; a drug for treating or preventing progress of symptoms, through inhibiting cell death, of sepsis; a drug for treating or preventing progress of symptoms, through inhibiting death of cells derived from bone marrow, of osteomyelo-dysplasia such as aplastic anemia and the like; a drug for treating or preventing progress of symptoms, through inhibiting cell death, of insulin dependent diabetes; a drug for treating or preventing progress of symptoms, through inhibiting death of neurons, of prion diseases; a drug for treating or preventing functional deficiency of transplanted organs, tissues or cells at transplantation of organs, tissues or cells; a preservative for organs, tissues and cells.
The following will explain the invention in detail.
The bisindolylpyrrole derivatives according to the invention can be synthesized according to the methods shown in Examples.
In the present description, the alkyl group in the xe2x80x9can alkyl group which may possess substituent(s)xe2x80x9d may be any of linear, branched, or cyclic one, and may be exemplified by an alkyl group having 1 to 30 carbon atoms, more concretely, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, 14-methylpentadecyl group, 6-methylpentadecyl group, octadecyl group, eicosyl group, tetracosyl group, and the like.
In the present description, the alkenyl group in the xe2x80x9can alkenyl group which may possess substituent(s)xe2x80x9d may be any of linear, branched, or cyclic one, and may be exemplified by an alkenyl group having 2 to 30 carbon atoms. Concrete examples thereof include allyl group, vinyl group, crotyl group, 1-penten-1-yl group, 2-penten-1-yl group, 3-penten-1-yl group, 1-hexen-1-yl group, 2-hexen-1-yl group, 3-hexen-1-yl group, 2-cyclohexenyl group, 2-cyclopentenyl group, 8-heptadecen-1-yl group, 8,11-heptadecadien-1-yl group, 8,11,14-heptadecatrien-1-yl group, 4,7,10,13-nonadecatetraen-1-yl group, 9-octadecen-1-yl group, 9,12-octadecadien-1-yl group, 9,12,15-octadecatrien-1-yl group, 6,9,12-octadecatrien-1-yl group, 5,8,11,14-eicosatetraen-1-yl group, 5,8,11,14,17-eicosapentaen-1-yl group, and 4,7,10,13,16,19-docosahexane-1-yl group.
In the present description, the alkynyl group in the xe2x80x9can alkynyl group which may possess substituent(s)xe2x80x9d may be any of linear, branched, or cyclic one, and may be exemplified by an alkynyl group having 2 to 30 carbon atoms. Concrete examples thereof include ethynyl group, propargyl group, 1-pentyn-1-yl group, 2-pentyn-1-yl group, 3-pentyn-1-yl group, 1-octyn-1-yl group, and 8-heptadecyn-1-yl group.
In the present description, the aryl group in the xe2x80x9can aryl group which may possess substituent(s)xe2x80x9d includes a heteroaryl group, and may be exemplified by phenyl group, naphthyl group, anthranyl group, pyrenyl group, biphenyl group, 4-pyridyl group, 2-pyridyl group, pyrimidinyl group, pyrazinyl group, piperazinyl group, pyrazolyl group, imidazolyl group, quinolyl group, pyrrolyl group, indolyl group, furyl group and the like.
In the present description, the acyl group in the xe2x80x9can acyl group which may possess substituent(s)xe2x80x9d or xe2x80x9can acyloxy group which may possess substituent(s)xe2x80x9d may be any of linear, branched, cyclic, saturated, unsaturated, aliphatic or aromatic one, and may be exemplified by an acyl group having 2 to 30 carbon atoms, more concretely, acetyl group, propionyl group, isopropionyl group, pivaloyl group, oleoyl group, cyclohexylcarbonyl group, acryloyl group, crotonoyl group, benzoyl group, naphthoyl group, nicotinoyl group, and the like.
In the present description, the alkoxy- or aryloxycarbonyl group in the xe2x80x9can alkoxy- or aryloxycarbonyl which may possess substituent(s)xe2x80x9d or xe2x80x9can alkoxy- or aryloxycarbonyloxy which may possess substituent(s)xe2x80x9d may be any of linear, branched, cyclic, saturated, unsaturated, aliphatic or aromatic one. The examples include methoxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group, isopropyloxycarbonyl group, butoxycarbonyl group, s-butoxycarbonyl group, t-butoxycarbonyl group, cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group, benzyloxycarbonyl group, allyloxycarbonyl group, phenyloxycarbonyl group, pyridyloxycarbonyl group, and the like.
In the present description, the alkyl- or arylthiocarbonyl group in the xe2x80x9can alkyl- or arylthiocarbonyl which may possess substituent(s)xe2x80x9d may be any of linear, branched, cyclic, saturated, unsaturated, aliphatic or aromatic one. The examples include methylthiocarbonyl group, ethylthiocarbonyl group, propylthiocarbonyl group, isopropylthiocarbonyl group, butylthiocarbonyl group, t-butylthiocarbonyl group, cyclopentylthiocarbonyl group, cyclohexylthiocarbonyl group, benzylthiocarbonyl group, phenylthiocarbonyl group, pyridylthiocarbonyl group, and the like.
In the present description, the aminocarbonyl group in the xe2x80x9can aminocarbonyl which may possess substituent(s)xe2x80x9d or xe2x80x9can aminocarbonyloxy which may possess substituent(s)xe2x80x9d may be an unsubstituted carbamoyl group, or an carbamoyl which is substituted by alkyl group(s) which may possess substituent(s), aromatic group(s) which may possess substituent(s), hydroxyl group, alkoxyl group(s) which may possess substituent(s), amino group(s) which may possess substituent(s), and the like. The examples include carbamoyl group, ethylaminocarbonyl group, propylaminocarbonyl group, isopropylaminocarbonyl group, butylaminocarbonyl group, t-butylaminocarbonyl group, cyclopentylaminocarbonyl group, cyclohexylaminocarbonyl group, benzylaminocarbonyl group, phenylaminocarbonyl group, pyridylaminocarbonyl group, and the like.
In the present description, the alkyl- or arylsulfonyl group in the xe2x80x9can alkyl or arylsulfonyl which may possess substituent(s)xe2x80x9d may be any of linear, branched, cyclic, saturated, unsaturated, aliphatic or aromatic one. The examples include methanesulfonyl group, ethanesulfonyl group, benzenesulfonyl group, cyclohexanesulfonyl group, naphthalenesulfonyl group, and the like.
In the present description, the alkyl- or arylsulfinyl group in the xe2x80x9can alkyl- or an arylsulfinyl which may possess substituent(s)xe2x80x9d may be any of linear, branched, cyclic, saturated, unsaturated, aliphatic or aromatic one. The examples include methanesulfinyl group, ethanesulfinyl group, benzenesulfinyl group, cyclohexanesulfinyl group, naphthalenesulfinyl group, and the like.
In the present description, the alkoxyl group or aryloxy group in the xe2x80x9can alkoxyl group or an aryloxy group which may possess substituent(s)xe2x80x9d may be any of linear, branched, cyclic, saturated, unsaturated, aliphatic or aromatic one, and may be exemplified by an alkoxy group or an aryloxy group having 2 to 30 carbon atoms. The particular examples include methoxy group, ethoxy group, propyloxy group, t-butoxy group, allyloxy group, cyclopentyloxy group, cyclohexyloxy group, benzyloxy group, phenoxy group, and the like.
In the present description, the alkyl- or arylthio group in the xe2x80x9can alkyl- or arylthio which may possess substituent( s)xe2x80x9d may be any of linear, branched, cyclic, saturated, unsaturated, aliphatic or aromatic one, and may be exemplified by an alkyl- or arylthio group having 2 to 30 carbon atoms. The particular examples include methylthio group, ethylthio group, propylthio group, t-butylthio group, allylthio group, cyclopentylthio group, cyclohexylthio group, benzylthio group, phenylthio group, and the like.
In the present description, the xe2x80x9can amino group which may possess substituent(s)xe2x80x9d may be an unsubstituted amino group, or an amino group which is substituted by alkyl group(s), aromatic group(s), and the like. The examples include ethylamino group, propylamino group, isopropylamino group, butylamino group, t-butylamino group, benzylamino group, phenylamino group, pyridylamino group, piperazinyl group, indolinyl group, and the like.
In the present description, xe2x80x9ca halogen atomxe2x80x9d may be fluorine atom, chlorine atom, bromine atom, and iodine atom.
The examples of substituents which may be present in the above-mentioned alkyl group, alkenyl group, alkynyl group, aryl group, acyl group, acyloxy group, alkoxy- or aryloxycarbonyl group, alkoxy- or aryloxycarbonyloxy group, alkylthio- or arylthiocarboyl group, aminocarbonyl group, aminocarbonyloxy group, alkoxyl group or aryloxy group, alkyl- or arylthio group, alkyl or arylsulfonyl group, alkyl or arylsulfinyl group, amino group, and the like include alkyl groups, alkenyl groups, alkynyl groups, aryl groups, acyl groups, acyloxy group, alkoxy- or aryloxycarbonyl group, alkoxy or aryloxycarbonyloxy group, alkylthio- or arylthiocarbonyl group, aminocarbonyl group, aminocarbonyloxy group, alkoxyl group, aryloxy group, alkyl- or arylthio group, alkyl- or arylsulfonyl group, alkyl- or arylsulfinyl group, and particular examples thereof are the same as mentioned above. The other substituents may be exemplified by halogen groups, nitro group, amino groups (which may possess substituent(s) such as acyl group(s), alkoxy- or aryloxycarbonyl group(s), carbamoyl group(s), substituted sulfonyl group(s), alkyl group(s), cycloalkyl group(s), aryl group(s), and the like), cyano group, hydroxyl group, carboxyl group, oxysulfonyl group, epoxy group and the like, as well as aralkyl groups such as benzyl group, phenethyl group, naphthylmethyl group, and the like.
As examples of two R3 groups or two R4 groups combined to form a hydrocarbon chain or a hydrocarbon chain containing heteroatom(s) which may possess substituent(s), rings fused to the benzene ring of the indole are represented. The fused ring may be exemplified by saturated or unsaturated aliphatic ring such as cyclopentane ring, cyclohexane ring, cyclohexene ring and the like; saturated or unsaturated heterocyclic ring such as pyrrolidine ring, tetrahydrofuran ring, imidazolidine ring, imidazoline ring, piperidine ring, morpholine ring, tetrahydrothiophene ring, and the like; aromatic ring such as benzene ring, naphthalene ring, indane ring, acenaphthene ring, fluorene ring, phenanthrene ring, and the like; heteroaromatic ring such as furan ring, thiophene ring, pyrrole ring, imidazole ring, pyridine ring, pyrimidine ring, pyradine ring, benzofuran ring, indole ring, quinoline ring, and the like.
As to the pharmaceutically acceptable salts, the compound having an acid part may formed a salt with an inorganic base or organic base, for example, an alkaline metal salt such as sodium salt, potassium salt, or the like; an alkaline earth metal salt such as calcium salt, magnesium salt, or the like; ammonium salt; an aliphatic or heteroaromatic amine salt such as triethylamine salt, ethanolamine salt, lysine salt, arginine salt, quinoline salt, pyridine salt or the like; a quaternary ammonium salt such as tetramethylammonium or the like. The compound having a basic part may form a salt with an inorganic or organic acid, for example, hydrochloride, bromate, iodate, sulfate, nitrate, phosphate, citrate, tartrate, malate, lactate, salicylate, malonate, fumarate, succiniate, oxalate, ascorbate, or the like.
The compound according to the invention may be applied as medicament in any form selected from various forms, for example, formulations for oral administration such as tablets, capsules, powders, granules, or liquids; and formulations for parenteral administration such as injections, rectal suppositories, formulations for external use on skin, inhalant, and the like.
Solid formulations can be prepared in a form of tablets, capsules, granules, or powders by themselves, or can be prepared with using suitable additive(s). Examples of such additives include sugars such as lactose or glucose; starches; fatty acids such as stearic acid; inorganic salts such as magnesium metasilicate aluminate or anhydrous calcium phosphate; synthetic polymers such as polyvinylpyrrolidone or polyalkylene glycol; fatty acid salts such as calcium stearate or magnesium stearate; alcohols such as stearyl alcohol or benzyl alcohol; synthetic cellulose derivatives such as methyl cellulose, ethyl cellulose, carboxymethyl cellulose, or hydroxypropyl cellulose; other conventional additives such as water, gelatin, talc, vegetable oils, acacia, or the like.
Liquid formulations are prepared in a form of suspensions, syrups, or injections by using suitable additive(s) conventionally used in liquid formulations such as water, alcohols, vegetable-derived oils including soybean oil, peanut oil, sesame oil, etc.
Especially, examples of suitable solvents for injections include distilled water for injection, aqueous lidocain hydrochloride solution, physiological saline, aqueous glucose solution, ethanol, liquids for intravenous injection such as aqueous solutions of citric acid and sodium citrate, electrolyte solution, and the like, or mixtures thereof. These injections may be a form of pre-dissolved one, and also a form for dissolving before use, which is composed of powder itself or powder with suitable additive(s).
The rectal suppositories may be prepared either by melting an active ingredient and base material(s) such as cacao butter, tri-, di- and monoglyceride of a fatty acid, polyethylene glycol, and the like under heating; charging the melt into a mold; and then cooling it; or by dissolving an active ingredient into polyethylene glycol, soybean oil, or the like and then covering it with gelatin film.
In the preparation of formulations for external use on skin, an active ingredient is added to vaseline, bees wax, liquid paraffin, polyethylene glycol, etc., followed by either kneading it, if necessary under heating, to form ointments, or kneading it with an adhesive such as rosin, a polymer of alkyl acrylate, etc. and spreading the kneaded one on unwoven cloth such as polyethylene or the like to form tapes.
In the preparation of inhalant, an active ingredient is dissolved or dispersed into a propellant such as flon gas, and then a pressure container is filled up to form aerosols.
Preferred dosage of the compound according to the invention varies depending on kinds of the compositions blended, dosing times and diseases to be treated, and also ages, body weights, and symptoms of patients, but may be ordinarily in an amount of about 1-1000 mg a day, preferably 5 to 500 mg, and they may be administered in one or several dosage units per day.
The organs relating to the invention may be all organs, such as heart, lung, liver, kidney, pancreas, and intestine.
The tissues relating to the invention may be all tissues, such as skin, cornea, bone marrow, vascular systems, and bone.
In the invention, cells expected to have effects on maintenance of the cell function by transplantation or the preservation may be all types of cells (normal various cells, immortalized cell lines, cancer cells, and cells that are modified by genetic recombination techniques for disease treatment and research purposes), such as vascular cells, islet cells of Langerhans, epidermal cells, neuronal cell, and embryonic stem cells.
As far as an administration method is concerned, when the chemical compounds according to the invention are used for the preservation of organs, tissues, and cells, various routes can be selected. For example, the present compound or a pharmaceutically acceptable salt thereof can be added to a culture medium or preservation solution containing appropriate salts and nutrients. In case of organ transplantation, it can be also administered intravenously or at perfusion to a donor prior to the organ isolation.